Influence of age and sex on physical, cardiac electrical and functional alterations in progressive hyperoxia treatment: A time course study in a murine model.

Oxygen supplementation is a widely used treatment for ICU patients. However, it can lead to hyperoxia, which in turn can result in oxidative stress, cardiac remodeling, and even mortality. This paper expands upon previous research conducted by our lab to establish time-dependent cardiac changes under hyperoxia. In this study, both young and aged mice (male and female) underwent 72 h of hyperoxia exposure and were monitored at 24-hour intervals for cardiac electrophysiological and functional parameters using ECG and electrocardiogram data. Our analysis showed that young male mice experienced significant weight loss as well as significant lung edema by 48 h. Although young male mice were highly susceptible to physical changes, they were resistant to early cardiac functional and electrophysiological changes compared to the other groups. Both young and aged female and aged males developed functional impairments by 24 h of hyperoxia exposure. Furthermore, sex and age differences were noted in the onset of electrophysiological changes. While some groups could resist early cardiac remodeling, our data suggests that 72 h of hyperoxia exposure is sufficient to induce significant cardiac remodeling across all age and sex groups. Our data establishes that time-dependent cardiac changes due to oxygen supplementation can have devastating consequences even with short exposure periods. These findings can aid in developing clinical practices for individuals admitted to the ICU by elucidating the impact of aging, sex, and length of stay under mechanical ventilation to limit hyperoxia-induced cardiac remodeling.

Prognostic impact of residual pulmonary congestion assessed by remote dielectric sensing system in patients admitted for heart failure.

AIMS: Remote dielectric sensing (ReDS) represents a contemporary non-invasive technique reliant on electromagnetic energy to quantify pulmonary congestion. Its prognostic significance within the context of heart failure (HF) patients remains elusive. This study aimed to assess the prognostic implications of residual pulmonary congestion, as gauged by the ReDS system, among patients admitted due to congestive HF. METHODS AND RESULTS: We enrolled hospitalized HF patients who underwent ReDS assessments upon admission and discharge in a blinded manner, independent of attending physicians. We evaluated the prognostic impact of the ReDS ratio between admission and discharge on the primary outcome, which encompassed all-cause mortality and HF-related re-hospitalizations. A cohort of 133 patients (median age 78 [72, 84] years, 78 male [59%]) was included. Over a median observation period of 363 days post-index discharge, an escalated ReDS group (ReDS ratio > 100%), determined through statistical calculation, emerged as an independent predictor of the primary outcome, exhibiting an adjusted hazard ratio of 4.37 (95% confidence interval 1.13-16.81, P = 0.032). The cumulative incidence of the primary outcome was notably higher in the increased ReDS group compared with the decreased ReDS group (50.1% vs. 8.5%, P = 0.034). CONCLUSIONS: Elevated ReDS ratios detected during the index hospitalization could serve as a promising prognostic indicator in HF patients admitted for treatment. The clinical ramifications of ReDS-guided HF management warrant validation in subsequent studies.

Fisiología respiratoria. Neumología de altura: saturación de oxígeno, edema pulmonar y pruebas de función pulmonar / Respiratory physiology - High -altitude pneumology: oxygen saturation, pulmonary edema and pulmonary function tests

En las alturas, sobre todo a 2500 metros sobre el nivel del mar, la cantidad absoluta de oxígeno va decreciendo y por lo tanto la cantidad disponible para el intercambio gaseoso disminuye, produciéndose una vasoconstricción hipóxica pulmonar (VHP). La VHP asociada a la hipoxia hipobárica de la altura produce un aumento de la presión pulmonar que es mayor en los lactantes y a mayores alturas. No hay valores únicos de saturación de oxígeno (SatO2) en la altura, porque ésta va disminuyendo según el mayor nivel de altura, aumenta con la edad, y la brecha entre la vigilia y sueño es grande (sobre todo en los primeros meses de vida). El 25% de los niños sanos que viven en altura tienen valores de SatO2 significativamente menores que el 75% restante. Los valores normales de los índices de apnea/hipopnea son distintos a los de nivel del mar. El edema pulmonar de las alturas es una patología frecuente, que se produce por un incremento desproporcionado en la VHP reflejando una hiperactividad del lecho vascular pulmonar ante la exposición aguda a la hipoxia hipobárica. Tiene cuatro fenotipos, es infrecuente en menores de 5 años y rara vez es mortal, la sospecha clínica y el manejo oportuno con oxigeno es la clave. Finalmente, en la altura los valores normales de la función pulmonar de la espirometría, oscilometría de impulso y capacidad de difusión son distintos que a nivel del mar.

At high altitude, especially > 2,500 meters above sea level, the absolute amount of oxygen decreases and therefore the amount available for gas exchange decreases, producing hypoxic pulmonary vasoconstriction (VHP). VHP associated with high-altitude hypobaric hypoxia produces an increase in pulmonary pressure that is greater in infants and at higher altitudes. There are no single values of oxygen saturation (SatO2) at altitude, because it decreases with the highest level of altitude, increases with age, and the gap between wakefulness and sleep is large (especially in the first months of life). Around 25% of healthy children living at altitude have SatO2 values significantly lower than the remaining 75%. The normal values of the apnea/hypopnea indices are different from those at sea level. High altitude pulmonary edema is a frequent pathology that is produced by a disproportionate increase in VHP reflecting hyperactivity of the pulmonary vascular bed in the face of acute exposure to hypobaric hypoxia, it has four phenotypes, it is uncommon in children under 5 years of age, and it is rarely fatal, the clinical suspicion and timely management with oxygen is the key. Finally, at high altitude, the normal values of lung function from spirometry, impulse oscillometry, and diffusing capacity are different from those at sea level.

What is the impact of microvascular complications of diabetes on severe COVID-19?

Evidence suggests severe coronavirus disease-19 (COVID-19) infection is characterised by pulmonary and systemic microvasculature dysfunction, specifically, acute endothelial injury, hypercoagulation and increased capillary permeability. Diabetes, which is also characterised by vascular injury in itself, confers an increased risk of adverse COVID-19 outcomes. It has been suggested that pre-existing endothelial dysfunction and microvascular disease in diabetes will exacerbate the vascular insults associated with COVID-19 and thus lead to increased severity of COVID-19 infection. In this article, we evaluate the current evidence exploring the impact of microvascular complications, in the form of diabetic retinopathy and nephropathy, in individuals with COVID-19 and diabetes. Future insights gained from exploring the microvascular injury patterns and clinical outcomes may come to influence care delivery algorithms for either of these conditions.

Post-exercise accumulation of interstitial lung water is greater in hypobaric than normobaric hypoxia in adults born prematurely.

We aimed to gauge the interstitial lung water accumulation following moderate-intensity exercise under normobaric and hypobaric hypoxic conditions in a group of preterm born but otherwise healthy young adults. Sixteen pre-term-born individuals (age = 21±2yrs.; gestational age = 29±3wk.; birth weight = 1160±273 g) underwent two 8 -h hypoxic/altitude exposures in a cross-over manner: 1) Normobaric hypoxic exposure (NH; FIO2 = 0.142±0.001; PIO2 = 90.6±0.9 mmHg) 2) Hypobaric hypoxic exposure (HH; terrestrial high-altitude 3840 m; PIO2 = 90.2±0.5 mmHg). Interstitial lung water was assessed via quantification of B-Lines (using lung ultrasound) before (normoxia) and after 4-h and 8-h of respective exposures. At each time point, B-Lines were quantified before (Pre) and immediately after (Post) a 6-min moderate-intensity exercise. The baseline B-lines count were comparable between both conditions (P = 0.191). A higher B-lines count was noted at Pre-H4 in HH versus NH (P = 0.0420). At Post-H8 B-lines score was significantly higher in HH (4.6 ± 1.6) than in NH (3.1 ± 1.4; P = 0.0073). Furthermore, at this time point, a significantly higher number of individuals with B-line scores ≥5 was observed in HH (n = 7) than in NH (n = 3; P = 0.0420). These findings suggest that short moderate-intensity exercise provokes a significant increase in the interstitial lung water accumulation after 8 h of exposure to terrestrial but not simulated altitude (≈3840 m) in prematurely born adults. Further work is needed to elucidate the exact mechanisms of (moderate-intensity) exercise-induced interstitial lung water accumulation in this population and directly compare the obtained data to full-term born adults.

Left ventricular depression and pulmonary edema in rats after short-term normobaric hypoxia: effects of adrenergic blockade and reduced fluid load.

Acute normobaric hypoxia may induce pulmonary injury with edema (PE) and inflammation. Hypoxia is accompanied by sympathetic activation. As both acute hypoxia and high plasma catecholamine levels may elicit PE, we had originally expected that adrenergic blockade may attenuate the severity of hypoxic pulmonary injury. In particular, we investigated whether administration of drugs with reduced fluid load would be beneficial with respect to both cardiocirculatory and pulmonary functions in acute hypoxia. Rats were exposed to normobaric hypoxia (10% O2) over 1.5 or 6 h and received 0.9% NaCl or adrenergic blockers either as infusion (1 ml/h, increased fluid load) or injection (0.5 ml, reduced fluid load). Control animals were kept in normoxia and received infusions or injections of 0.9% NaCl. After 6 h of hypoxia, LV inotropic function was maintained with NaCl injection but decreased significantly with NaCl infusion. Adrenergic blockade induced a similar LV depression when fluid load was low, but did not further deteriorate LV depression after 6 h of infusion. Reduced fluid load also attenuated pulmonary injury after 6 h of hypoxia. This might be due to an effective fluid drainage into the pleural space. Adrenergic blockade could not prevent PE. In general, increased fluid load and impaired LV inotropic function promote the development of PE in acute hypoxia. The main physiologic conclusion from this study is that fluid reduction under hypoxic conditions has a protective effect on cardiopulmonary function. Consequently, appropriate fluid management has particular importance to subjects in hypoxic conditions.

Changes in Expressions of HSP27, HSP70, and Soluble Glycoprotein in Heart Failure Rats Complicated with Pulmonary Edema and Correlations with Cardiopulmonary Functions.

The study is aimed at investigating the changes in expressions of heat shock protein 27 (HSP27), HSP70, and soluble glycoprotein (SGP) in heart failure (HF) rats complicated with pulmonary edema and exploring their potential correlations with cardiopulmonary functions. The rat model of HF was established, and the rats were divided into HF model group (model group, n = 15) and normal group (n = 15). After successful modeling, MRI and ECG were applied to detect the cardiac function indexes of the rats. The myocardial function indexes were determined, the injury of myocardial tissues was observed via hematoxylin and eosin (HE) staining, and the content of myeloperoxidase (MPO), matrix metalloproteinase-9 (MMP-9), and tumor necrosis factor-alpha (TNF-α) in the blood was measured. The partial pressure of oxygen (PaO2) and oxygenation index (OI) were observed, and the airway resistance and lung compliance were examined. Moreover, quantitative polymerase chain reaction (qPCR) and Western blotting assay were performed to detect the gene and protein expression levels of HSP27, HSP70, and SGP130. The levels of serum creatine kinase (CK), creatine (Cr), and blood urea nitrogen (BUN) were increased markedly in model group (p < 0.05). Model group had notably decreased fractional shortening (FS) and ejection fraction (EF) compared with normal group (p < 0.05), while the opposite results of left ventricular end-diastolic diameter (LVEDD) and left ventricular end-systolic diameter (LVESD) were detected. In model group, the content of serum MPO, MMP-9, and TNF-α was raised remarkably (p < 0.05), OI and PaO2 were reduced notably (p < 0.05), the airway resistance was increased (p < 0.05), and the lung compliance was decreased (p < 0.05). Obviously elevated gene and protein expression levels of HSP27, HSP70, and SGP130 were detected in model group (p < 0.05). The expressions of HSP27, HSP70, and SGP130 are increased in HF rats complicated with pulmonary edema, seriously affecting the cardiopulmonary functions of the rats.

Acute pulmonary edema due to severe preeclampsia in advanced maternal age women.

OBJECTIVE: Acute pulmonary edema is a rare complication in women with preeclampsia especially at advanced maternal age. We aimed to determine the cardiovascular hemodynamics in advanced maternal age women who developed acute pulmonary edema and preeclampsia. STUDY DESIGN: Retrospective cohort study of women aged over 45 years giving birth at single university affiliated tertiary medical center which developed acute pulmonary edema due to severe preeclampsia. Clinical features were identified in order to predict and potentially prevent this severe complication of pregnancy. MAIN OUTCOME MEASURES: Advanced maternal age women who developed acute pulmonary edema due to preeclampsia. RESULTS: Overall, during the study period 90,540 women delivered in our hospital, of them, 540 women (0.6%) above the age of 45 years gave birth. Of those, 67 women (12.4%) had preeclampsia in which 4 women (6%) were complicated with acute pulmonary edema. The common clinical relevant characteristics for all four women were: preterm delivery by cesarean section for preeclampsia with severe features, non-restrictive fluid management around the time of delivery, post-partum pain control medication with non-steroidal anti-inflammatory drug, blood pressure stabilization with oral labetalol and a sudden hemodynamic deterioration to hypertensive crisis and pulmonary edema between post-operative days 4-9. CONCLUSION: Although the precise trigger for the sudden presentation of acute pulmonary edema remains unknown, we suggest that there is a multi-factorial combination of etiologies that are common to women of advanced maternal age and women with preeclampsia that could have contributed to the development of pulmonary edema.

The Young Elite Swimmer and the Lung: An Editorial / El joven nadador de élite y el pulmón; un editorial

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Point-of-Care Lung Ultrasound Pattern in Healthy Parturients: Prevalence of Pulmonary Interstitial Syndrome Following Vaginal Delivery, Elective and Unplanned Intrapartum Cesarean Delivery.

BACKGROUND: Pregnancy-related cardiovascular physiologic changes increase the likelihood of pulmonary edema, with the risk of fluid extravasating into the pulmonary interstitium being potentially at a maximum during the early postpartum period. Data on the impact of labor and peripartum hemodynamic strain on lung ultrasound (LUS) are limited, and the prevalence of subclinical pulmonary interstitial syndrome in peripartum women is poorly described. The primary aim of this exploratory study was to estimate the prevalence of pulmonary interstitial syndrome in healthy term parturients undergoing vaginal (VD), elective (eCD), and unplanned intrapartum cesarean deliveries (uCD). Secondary aims were to estimate the prevalence of positive lung regions (≥3 B-lines on LUS per region) and to assess the associations between positive lung regions and possible contributing factors. METHODS: In this prospective observational cohort study, healthy women at term undergoing VD, eCD, or uCD were enrolled. Following international consensus recommendations, a LUS examination was performed within 4 hours after delivery applying an 8-region technique. Pulmonary interstitial syndrome was defined by the presence of 2 or more positive lung regions per hemithorax. Ultrasound studies were reviewed by 2 blinded reviewers and assessed for interobserver reliability. RESULTS: Seventy-five women were assessed (n = 25 per group). No pulmonary interstitial syndrome was found in the VD and eCD groups (each 0 of 25; 0%, 95% confidence interval [CI], 0-13.7). Pulmonary interstitial syndrome was found in 2 of 25 (8%, 95% CI, 1-26) women undergoing an uCD (P = .490 for VD versus uCD and P = .490 for eCD versus uCD). In 1 woman, this correlated clinically with the development of pulmonary edema. One or more positive lung regions were present in 5 of 25 (20%), 6 of 25 (24%), and 11 of 25 (44%) parturients following VD, eCD, and uCD, respectively (P = .136). Positive lung regions were predominantly found in lateral lung regions. The number of positive lung regions showed a weak correlation with patient age (r = 0.25, 95% CI, 0.05-0.47; P = .033). No significant association was found between LUS pattern and parity, duration of labor, labor augmentation, labor induction, estimated total intravenous fluid intake, or net intravenous fluid intake. CONCLUSIONS: Although many focal areas of increased extravascular lung water (20%-44% prevalence) can be identified on LUS, the overall prevalence of pulmonary interstitial syndrome was 2.7% (2 of 75; 95% CI, 0.3-9.3) among healthy term parturients soon after delivery. Focal areas of positive lung water regions were weakly correlated with maternal age.

Standardization of methods for sampling the distal airspace in mechanically ventilated patients using heat moisture exchange filter fluid.

Noninvasive sampling of the distal airspace in patients with acute respiratory distress syndrome (ARDS) has long eluded clinical and translational researchers. We recently reported that fluid collected from heat moisture exchange (HME) filters closely mirrors fluid directly aspirated from the distal airspace. In the current study, we sought to determine fluid yield from different HME types, optimal HME circuit dwell time, and reliability of HME fluid in reflecting the distal airspace. We studied fluid yield from four different filter types by loading increasing volumes of saline and measuring volumes of fluid recovered. We collected filters after 1, 2, and 4 h of dwell time for measurement of fluid volume and total protein from 13 subjects. After identifying 4 h as the optimal dwell time, we measured total protein and IgM in HME fluid from 42 subjects with ARDS and nine with hydrostatic pulmonary edema (HYDRO). We found that the fluid yield varies greatly by filter type. With timed sample collection, fluid recovery increased with increasing circuit dwell time with a median volume of 2.0 mL [interquartile range (IQR) 1.2-2.7] after 4 h. Total protein was higher in the 42 subjects with ARDS compared with nine with HYDRO [median 708 µg/mL (IQR 244-2017) vs. 364 µg/mL (IQR 136-578), P = 0.047], confirming that total protein concentration in HME is higher in ARDS compared with hydrostatic edema. These studies establish a standardized HME fluid collection protocol and confirm that HME fluid analysis is a novel noninvasive tool for the study of the distal airspace in ARDS.

Cerebral perfusion pressure and autoregulation in eclampsia-a case control study.

BACKGROUND: Dynamic cerebral autoregulation and cerebral perfusion pressure are altered in pregnancies complicated by preeclampsia compared with normotensive pregnancies, but the connections of dynamic cerebral autoregulation, cerebral perfusion pressure, and cerebral complications in preeclampsia remain unclear. OBJECTIVE: This study aimed to assess dynamic cerebral autoregulation and cerebral perfusion pressure after delivery in women with eclampsia, in women with preeclampsia both with and without severe features, and in normotensive women. STUDY DESIGN: This was a prospective case control study at a large referral hospital in Cape Town, South Africa. The recruitment of participants was done at diagnosis (cases) or at admission for delivery (controls). Transcranial Doppler examinations with continuous noninvasive blood pressure measurements and end-tidal CO2 monitoring were conducted for cases and controls after delivery. Cerebral perfusion pressure and dynamic cerebral autoregulation index were calculated, and values were compared among groups. RESULTS: We included 16 women with eclampsia, 18 women with preeclampsia with severe features, 32 women with preeclampsia without severe features, and 21 normotensive women with uncomplicated pregnancies. Dynamic cerebral autoregulation was depressed in pregnant women with eclampsia; (autoregulation index, 3.9; interquartile range, 3.1-5.2) compared with all other groups (those with preeclampsia with severe features, autoregulation index, 5.6 [interquartile range, 4.4-6.8]; those with preeclampsia without severe features, autoregulation index, 6.8 [interquartile range, 5.1-7.4]; and normotensive controls, autoregulation index, 7.1 [interquartile range, 6.1-7.9]). Pregnant women with eclampsia had increased cerebral perfusion pressure (109.5 mm Hg; interquartile range, 91.2-130.9) compared with those with preeclampsia without severe features and those with normal blood pressure (84 mm Hg [interquartile range, 73.0-122.0] and 80.0 mm Hg [interquartile range, 67.5-92.0], respectively); furthermore, there was no difference in cerebral perfusion pressure between pregnant women with eclampsia and pregnant women with preeclampsia with severe features (109.5 mm Hg [interquartile range, 91.2-130.9] vs 96.5 mm Hg [interquartile range, 75.8-110.5]). CONCLUSION: Cerebral perfusion pressure and dynamic cerebral autoregulation are altered in eclampsia and may be important in the pathophysiological pathway and constitute a therapeutic target in the prevention of cerebral complications in preeclampsia.

Severe acute respiratory syndrome coronavirus-2- or pregnancy-related cardiomyopathy, a differential to be considered in the current pandemic: a case report.

BACKGROUND: There are limited data on cardiovascular complications of coronavirus disease 2019 in pregnancy, and there are only a few case reports on coronavirus disease 2019 related cardiomyopathy in pregnancy. Differentiation between postpartum cardiomyopathy and coronavirus disease 2019 related cardiomyopathy in pregnant women who develop severe acute respiratory syndrome coronavirus-2 infection during peripartum could be challenging. Here, we present a case of possible coronavirus disease 2019 related cardiomyopathy in a pregnant patient, followed by a discussion of potential differential diagnosis. CASE PRESENTATION: In this case report, we present the case of a young pregnant Iranian woman who developed heart failure with pulmonary edema after cesarean section. She was treated because of low left ventricular ejection fraction and impression of postpartum cardiomyopathy, and her severe dyspnea improved by intravenous furosemide. On day 3, she exhibited no orthopnea or leg edema, but she was complaining of severe and dry cough. Further evaluation showed severe acute respiratory syndrome coronavirus-2 infection. CONCLUSIONS: The possibility of severe acute respiratory syndrome coronavirus-2 infection should be considered in any pregnant woman who develops cardiomyopathy and pulmonary edema.

The fluid management and hemodynamic characteristics of PiCCO employed on young children with severe hand, foot, and mouth disease-a retrospective study.

BACKGROUND: Hand, foot, and mouth disease (HFMD) is an acute infectious disease caused by human enterovirus 71 (EV71), coxsackievirus, or echovirus, which is particularly common in preschool children. Severe HFMD is prone to cause pulmonary edema before progressing to respiratory and circulatory failure; thus hemodynamic monitoring and fluid management are important to the treatment process. METHODS: We did a review of young patients who had been successfully treated in our department for severe HFMD, which had been caused by EV71. A total of 20 patients met the inclusion criteria. Eight cases were monitored by the pulse indicator continuous cardiac output (PiCCO) technique, and fluid management was administered according to its parameters. With regard to the treatment with PiCCO monitoring, patients were divided into two groups: the PiCCO group (8 patients) and the control group (12 patients). The groups were then compared comprehensively to evaluate whether PiCCO monitoring could improve patients' clinical outcomes. RESULTS: After analysis, the findings informed that although PiCCO failed to shorten the length of ICU stay, reduce the days of vasoactive drug usage, or lower the number of cases which required mechanical ventilation, PiCCO did reduce the incidence of fluid overload (p = 0.085) and shorten the days of mechanical ventilation (p = 0.028). After effective treatment, PiCCO monitoring indicated that the cardiac index (CI) increased gradually(p < 0.0001), in contrast to their pulse (P, p < 0.0001), the extra vascular lung water index (EVLWI, p < 0.0001), the global end diastolic volume index (GEDVI, p = 0.0043), and the systemic vascular resistance index (SVRI, p < 0.0001), all of which decreased gradually. CONCLUSION: Our study discovered that PiCCO hemodynamic monitoring in young children with severe HFMD has some potential benefits, such as reducing fluid overload and the duration of mechanical ventilation. However, whether it can ameliorate the severity of the disease, reduce mortality, or prevent multiple organ dysfunction remain to be further investigated.

Effects of Lung Ultrasonography-Guided Management on Cumulative Fluid Balance and Other Clinical Outcomes: A Systematic Review.

Lung ultrasonography is accurate in detecting pulmonary edema and overcomes most limitations of traditional diagnostic modalities. Whether use of lung ultrasonography-guided management has an effect on cumulative fluid balances and other clinical outcomes remains unclear. In this systematic review, we included 12 studies using ultrasonography guided-management with a total of 2290 patients. Four in-patient studies found a reduced cumulative fluid balance (ranging from -0.3 L to -2.4 L), whereas three out-patient studies found reduction in dialysis dry weight (ranging from -2.6 kg to -0.2 kg) compared with conventionally managed patients. None of the studies found adverse effects related to hypoperfusion. The use of lung ultrasonography-guided management was not associated with other clinical outcomes. This systematic review shows that lung ultrasonography-guided management, exclusively or in concert with other diagnostic modalities, is associated with a reduced cumulative fluid balance. Studies thus far have not shown a consistent effect on clinical outcomes.

Severe acute mitral valve regurgitation in a COVID-19-infected patient.

The ongoing SARS-CoV-2 (COVID-19) pandemic has presented many difficult and unique challenges to the medical community. We describe a case of a middle-aged COVID-19-positive man who presented with pulmonary oedema and acute respiratory failure. He was initially diagnosed with acute respiratory distress syndrome. Later in the hospital course, his pulmonary oedema and respiratory failure worsened as result of severe acute mitral valve regurgitation secondary to direct valvular damage from COVID-19 infection. The patient underwent emergent surgical mitral valve replacement. Pathological evaluation of the damaged valve was confirmed to be secondary to COVID-19 infection. The histopathological findings were consistent with prior cardiopulmonary autopsy sections of patients with COVID-19 described in the literature as well as proposed theories regarding ACE2 receptor activity. This case highlights the potential of SARS-CoV-2 causing direct mitral valve damage resulting in severe mitral valve insufficiency with subsequent pulmonary oedema and respiratory failure.

CRD-733, a Novel PDE9 (Phosphodiesterase 9) Inhibitor, Reverses Pressure Overload-Induced Heart Failure.

BACKGROUND: Augmentation of NP (natriuretic peptide) receptor and cyclic guanosine monophosphate (cGMP) signaling has emerged as a therapeutic strategy in heart failure (HF). cGMP-specific PDE9 (phosphodiesterase 9) inhibition increases cGMP signaling and attenuates stress-induced hypertrophic heart disease in preclinical studies. A novel cGMP-specific PDE9 inhibitor, CRD-733, is currently being advanced in human clinical studies. Here, we explore the effects of chronic PDE9 inhibition with CRD-733 in the mouse transverse aortic constriction pressure overload HF model. METHODS: Adult male C57BL/6J mice were subjected to transverse aortic constriction and developed significant left ventricular (LV) hypertrophy after 7 days (P<0.001). Mice then received daily treatment with CRD-733 (600 mg/kg per day; n=10) or vehicle (n=17), alongside sham-operated controls (n=10). RESULTS: CRD-733 treatment reversed existing LV hypertrophy compared with vehicle (P<0.001), significantly improved LV ejection fraction (P=0.009), and attenuated left atrial dilation (P<0.001), as assessed by serial echocardiography. CRD-733 prevented elevations in LV end diastolic pressures (P=0.037) compared with vehicle, while lung weights, a surrogate for pulmonary edema, were reduced to sham levels. Chronic CRD-733 treatment increased plasma cGMP levels compared with vehicle (P<0.001), alongside increased phosphorylation of Ser273 of cardiac myosin binding protein-C, a cGMP-dependent protein kinase I phosphorylation site. CONCLUSIONS: The PDE9 inhibitor, CRD-733, improves key hallmarks of HF including LV hypertrophy, LV dysfunction, left atrial dilation, and pulmonary edema after pressure overload in the mouse transverse aortic constriction HF model. Additionally, elevated plasma cGMP may be used as a biomarker of target engagement. These findings support future investigation into the therapeutic potential of CRD-733 in human HF.

The impact of the definition of preeclampsia on disease diagnosis and outcomes: a retrospective cohort study.

BACKGROUND: The diagnostic criteria for preeclampsia have evolved from the traditional definition of de novo hypertension and proteinuria to a broader definition of hypertension with evidence of end-organ dysfunction. Although this change is endorsed by various societies such as the International Society for the Study of Hypertension in Pregnancy and the American College of Obstetricians and Gynecologists, there remains controversy with regard to the implementation of broader definitions and the most appropriate definition of end-organ dysfunction. OBJECTIVE: This study aimed to assess the impact of different diagnostic criteria for preeclampsia on rates of disease diagnosis, disease severity, and adverse outcomes and to identify associations between each component of the different diagnostic criteria and adverse pregnancy outcomes. STUDY DESIGN: We performed a retrospective cohort study of singleton pregnancies at Monash Health between January 1, 2016 and July 31, 2018. Within this population, all cases of gestational hypertension and preeclampsia were reclassified according to the International Society for the Study of Hypertension in Pregnancy 2001, American College of Obstetricians and Gynecologists 2018, and International Society for the Study of Hypertension in Pregnancy 2018 criteria. Differences in incidence of preeclampsia and maternal and perinatal outcomes were compared between the International Society for the Study of Hypertension in Pregnancy 2001 group and the extra cases identified by American College of Obstetricians and Gynecologists 2018 and International Society for the Study of Hypertension in Pregnancy 2018. Outcomes assessed included biochemical markers of preeclampsia, a composite of adverse maternal outcomes, and a composite of adverse perinatal outcomes. Multiple logistic regression analysis was also performed to assess each component of the American College of Obstetricians and Gynecologists 2018 and International Society for the Study of Hypertension in Pregnancy 2018 criteria and their associations with adverse maternal and perinatal outcomes. RESULTS: Of 22,094 pregnancies, 751 (3.4%) women had preeclampsia as defined by any of the 3 criteria. Compared with International Society for the Study of Hypertension in Pregnancy 2001, the American College of Obstetricians and Gynecologists 2018 criteria identified an extra 42 women (n=654 vs n=696, 6.4% relative increase) with preeclampsia, and International Society for the Study of Hypertension in Pregnancy 2018 identified an extra 97 women (n=654 vs n=751, 14.8% relative increase). The additional women identified by International Society for the Study of Hypertension in Pregnancy 2018 exhibited a milder form of disease with lower rates of severe hypertension (62.4% vs 44.3%; P<.01) and magnesium sulfate use (11.9% vs 4.1%; P<.05) and a trend toward lower rates of adverse maternal outcomes (9.8% vs 4.1%). These women also delivered at a later gestation, and their babies had a lower number of neonatal intensive care unit admissions and adverse perinatal outcomes. Objective features such as fetal growth restriction, thrombocytopenia, renal and liver impairment, and proteinuria were associated with an increased risk of adverse maternal and perinatal outcomes, whereas subjective neurologic features demonstrated poorer associations. CONCLUSION: Implementation of broader definitions of preeclampsia will result in an increased incidence of disease diagnosis. However, because women who exclusively fulfill the new criteria have a milder phenotype of the disease, it remains uncertain whether this will translate to improved outcomes.

Systematic Review of Negative Pressure Pulmonary Edema in Otolaryngology Procedures.

OBJECTIVE(S): Negative pressure pulmonary edema (NPPE) is a rare perioperative complication with a potentially fatal outcome. The aim of this study was to perform a systematic review of NPPE in adult otolaryngology procedures with the goal of identifying risk factors, clinical presentation, diagnosis, management and outcomes. METHODS: Systematic review performed using PubMed, Scopus, Web of Science, and Cochrane databases. RESULTS: Sixty-nine studies including data from 87 individual patients were included in this review. Fifty-six (68%) patients were male and the average patient age was 37 years old. Type 1 NPPE occurred in 63 (72%) cases, while type 2 NPPE accounted for 20 (23%) cases. The most common procedures leading to NPPE were septoplasty, rhinoplasty or sinus surgery (n = 22, 25%), directly laryngoscopy or bronchoscopy (n = 13, 15%), and tracheostomy or cricothyroidotomy (n = 11, 13%). The most employed treatment options included diuretics (n = 55, 63%) and mechanical ventilation (n = 54, 62%). Seventy-eight (90%) patients made a full recovery with an average time to NPPE resolution of 33 hours and an average length of hospitalization of 5.6 days. Five (6%) patients had a long-term morbidity and four (5%) patients died, with age and ICU stay increasing risk for death and long-term morbidity (OR 1.044 and 7.42, respectively, P < .05). CONCLUSION: Septoplasty, rhinoplasty and sinus surgery account for the majority of NPPE cases in adult otolaryngology procedures. Young, healthy patients are the most commonly involved with a slight male predominance. The vast majority of patients recover fully, however there is a significant risk for morbidity and mortality.